Much laboratory and clinical research has focused on the development of treatment for Herpes simplex virus (HSV)-induced disease. There is, however, still no therapeutic agent available which could be considered unequivocally safe and effective in humans, particularly the orofacial and other cutaneous manifestations of herpetic infection. The present proposal is the investigation of a new antiviral nucleoside analogue, aciclovir (ACV), the nucleoside antiviral, vidarabine (ara-A), and its antiviral nucleotide derivative, vidarabine monophosphate (ara-AMP). The topical and systemic efficacy of these compounds in the treatment of experimental primary orofacial, skin and brain HSV infections will be evaluated by clinical, virologic and histopathologic means. Furthermore, the therapeutic effect of these antivirals in reducing or eliminating HSV ganglionic latency will be studied. Because HSV latent infection is located in the ganglia far from the primary or recurrent HSV clinical lesions, systemic therapy must be considered for the control of this reservoir which serves as the source of recurrent infection. ACV, by virtue of its potent antiherpetic effectiveness, its lack of toxicity, and its specific mode of action, is a promising candidate for the systemic therapy. Ara-A, already known as a relatively less toxic systemic antiherpetic agent, and ara-AMP, a highly soluble and active form of ara-A, could be considered as relatively safe antiviral agents for systemic administration. The latent HSV infection in laboratory animals, therefore, will be challenged by systemic administration of the antivirals. Their effect on the persistence of latent virus in the sensory ganglia will be determined. In addition to their therapeutic evaluation, possible toxicologic studies will also be performed by histopathologic analysis.